Xanthylium, 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethyl-, molybdatetungstatephosphate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated forXanthylium, 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethyl-, molybdate tungstate phosphate (12224-98-5).Male and female reproductive parameters were unaffected by test material administration. Hence NOAEL was estimated to be 481.595mg/kg bw. When male and female Sprague-Dawley rats were exposed with Xanthylium, 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethyl-, molybdate tungstate phosphate (12224-98-5) orally. Thus, based on the above predictions and experimental study on Xanthylium, 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethyl-, molybdate tungstate phosphate (12224-98-5) and its structurally and functionally similar read across substance D&C YELLOW NO. 8 (518-47-8) in two different rodent species i.e rats and rabbits oral route, no adverse effects on reproductive and developmental parameter were observed. Thus, comparing this value with the criteria of CLP regulation Xanthylium, 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethyl-, molybdate tungstate phosphate (12224-98-5) cannot be classified as reproductive toxicant.

 

Link to relevant study records

Reference

Endpoint:

toxicity to reproduction

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification

Justification for type of information:

Data is from OECD QSAR toolbox v3.3 and the QMRF report has been attached.

Qualifier:

equivalent or similar to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.3, 2017

GLP compliance:

not specified

Limit test:

no

Justification for study design:

No data available

Specific details on test material used for the study:

- Name of test material (as cited in study report): C.I. Pigment red 81
- IUPAC name: Xanthylium, 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethyl-, molybdatetungstatephosphate
- Molecular formula: C28H31N2O3.x-Unspecified
- Molecular weight: 443.5639 g/mol
- Smiles: CCNc1cc2c(cc1C)c(c3cc(c(cc3[o+]2)NCC)C)c4ccccc4C(=O)OCC
- InChI: 1S/C28H31N2O3/c1-6-29-23-15-25-21(13-17(23)4)27(19-11-9-10-12-20(19)28(31)32-8-3)22-14-18(5)24(30-7-2)16-26(22)33-25/h9-16, 29-30H,6-8H2,1-5H3/q+1
- Substance type: Organic
- Physical state: Solid powder (dark pink)

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

No data available

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data available

Route of administration:

oral: feed

Type of inhalation exposure (if applicable):

other: NOT_SPECIFIED

Vehicle:

not specified

Details on exposure:

No data available

Details on mating procedure:

No data available

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

90 days

Frequency of treatment:

continuously with the diet

Details on study schedule:

No data available

Dose / conc.:

481.595 mg/kg bw/day (nominal)

No. of animals per sex per dose:

28 (P), 24 (F1)

Control animals:

not specified

Details on study design:

No data available

Positive control:

No data available

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule:
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule:

BODY WEIGHT: Yes
- Time schedule for examinations:

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / No data
- Time schedule for examinations:

OTHER:

Oestrous cyclicity (parental animals):

No data available

Sperm parameters (parental animals):

No data available

Litter observations:

No data available

Postmortem examinations (parental animals):

No data available

Postmortem examinations (offspring):

No data available

Statistics:

No data available

Reproductive indices:

No data available

Offspring viability indices:

No data available

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Dose descriptor:

NOAEL

Effect level:

481.595 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

body weight and weight gain

food consumption and compound intake

reproductive function (sperm measures)

Remarks on result:

other: No effects on reproductive performance

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

not specified

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

481.595 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

body weight and weight gain

gross pathology

Remarks on result:

other: overall developmental effects not observed

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Reproductive effects observed:

not specified

Treatment related:

not specified

Relation to other toxic effects:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

The prediction was based on dataset comprised from the following descriptors: NOAEL
Estimation method: Takes average value from the 7 nearest neighbours
Domain  logical expression:Result: In Domain

(((((("a" or "b" or "c" or "d" )  and ("e" and ( not "f") )  )  and ("g" and ( not "h") )  )  and ("i" and ( not "j") )  )  and ("k" and ( not "l") )  )  and ("m" and "n" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Esters (Chronic toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as SN1 AND SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Secondary aromatic amine by DNA binding by OECD

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Esters by Acute aquatic toxicity MOA by OASIS

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Esters by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.3

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds >> Four- and Five-Membered Lactones OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation >> Geminal Polyhaloalkane Derivatives OR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR AN2 >> Shiff base formation for aldehydes OR AN2 >> Shiff base formation for aldehydes >> Geminal Polyhaloalkane Derivatives OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Coumarins OR Radical OR Radical >> Generation of ROS by glutathione depletion (indirect) OR Radical >> Generation of ROS by glutathione depletion (indirect) >> Haloalkanes Containing Heteroatom OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Coumarins OR Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives OR SN1 OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters OR SN2 >> Acylation involving a leaving group  OR SN2 >> Acylation involving a leaving group  >> Geminal Polyhaloalkane Derivatives OR SN2 >> Acylation involving a leaving group after metabolic activation OR SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives OR SN2 >> Alkylation, direct acting epoxides and related OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines OR SN2 >> Alkylation, ring opening SN2 reaction OR SN2 >> Alkylation, ring opening SN2 reaction >> Four- and Five-Membered Lactones OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Coumarins OR SN2 >> DNA alkylation OR SN2 >> DNA alkylation >> Alkylphosphates, Alkylthiophosphates and Alkylphosphonates OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Haloalkanes Containing Heteroatom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation >> Geminal Polyhaloalkane Derivatives by DNA binding by OASIS v.1.3

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Moderate binder, OH grooup OR Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure OR Strong binder, OH group OR Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.3

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Michael Addition OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-Carbonyl compounds with polarized double bonds  OR SN2 OR SN2 >> SN2 Reaction at a sp3 carbon atom OR SN2 >> SN2 Reaction at a sp3 carbon atom >> Activated alkyl esters and thioesters  by Protein binding by OASIS v1.3

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OECD

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct Acylation Involving a Leaving group OR Acylation >> Direct Acylation Involving a Leaving group >> Acetates by Protein binding by OECD

Domain logical expression index: "m"

Parametric boundary:The target chemical should have a value of log Kow which is >= 2.1

Domain logical expression index: "n"

Parametric boundary:The target chemical should have a value of log Kow which is <= 10.4

Conclusions:

In reproductive toxicity study, NOAEL was estimated to be 481.595mg/kg bw. When male and female Sprague-Dawley rats were exposed with Xanthylium, 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethyl-, molybdate tungstate phosphate (12224-98-5) orally.

Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated forXanthylium, 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethyl-, molybdate tungstate phosphate (12224-98-5).Male and female reproductive parameters were unaffected by test material administration. HenceNOAEL was estimated to be 481.595mg/kg bw. When male and female Sprague-Dawley rats were exposed with Xanthylium, 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethyl-, molybdate tungstate phosphate (12224-98-5) orally.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

481.595 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is Klimicsh 2 and from QSAR Toolbox 3.3. (2017)

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Toxicity to reproduction

In different studies Xanthylium, 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethyl-, molybdate tungstate phosphate (12224-98-5)has been investigated for reproductive toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments and estimated data in rodents, i.e. most commonly in rats for Xanthylium, 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethyl-, molybdate tungstate phosphate (12224-98-5).The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies performed on structurally and functionally similar read across substance

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for Xanthylium, 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethyl-, molybdate tungstate phosphate (12224-98-5).Male and female reproductive parameters were unaffected by test material administration. Hence NOAEL was estimated to be 481.595mg/kg bw. When male and female Sprague-Dawley rats were exposed with Xanthylium, 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethyl-, molybdate tungstate phosphate (12224-98-5) orally.

Also supported by experimental study conducted by C. M. BURNETI, E. I. GOLDENTHAL (Fd Chem. Toxic, Vol. 24, No. 8, pp. 819 823, 1986) on structurally and functionally similar read across substance D & C Yellow No. 8 (518-47-8). In a Teratogenic Potential Test, CD Sprague-Dawley female rats treated with D & C Yellow No. 8, sodium fluorescein in the concentration of 0, 100, 500 or 1500 mg/kg bw orally by gavage in water for 14 days (days 6-19 of gestation). Six rats died during the dosing period at 1500 mg/kg bw as compared to control. Survival was 100% in the controls and the groups receiving 100 and 500 mg/kg of dye. Slight reductions in body-weight gains at 1500 mg/kg bw and Orange discoloration of the urine was noted in all treated rats during the treatment period. No effect on reproductive parameters such as Viable and non-viable fetuses, early and late resorptions, total implantations and corpora lutea and sex ratio of fetuses were observed in treated female rats as compared to control. Green discoloration of the amniotic fluid was observed in 1, 10 and 16 rats at 100, 500 and 1500 mg/kg/day groups, respectively, and the small intestines were green in colour in many rats at 500 mg/Kg group. In addition, No effect on Body weight of fetuses were observed as compared to control. A slight increase in the number of litters with unossified sternebrae (sternebrae nos 1-6) and rudimentary 14th rib(s) was observed at 1500 mg/kg bw however, these values fell within the ranges of historical control data. No biologically meaningful or statistically significant differences in the number of litters and number of fetuses with malformations and number of fetuses or litters with developmental variations were observed in treated rats as compared to control. Therefore, NOAEL was considered to be 1500 mg/kg/day for P and F1 generation when CD Sprague-Dawley female rats treated with D & C Yellow No. 8, sodium fluorescein orally by gavage for 14 days. 

Also further supported by   experimental study conducted by C. M. BURNETI, E. I. GOLDENTHAL (Fd Chem. Toxic, Vol. 24, No. 8, pp. 819 823, 1986) on structurally similar read across substance D & C Yellow No. 8 (518-47-8). In a reproductive and developmental toxicity study, Dutch Belted female Rabbits were treated with D&C YELLOW NO. 8 (518-47-8) in the concentration of0, 30, 100 and 250 mg/kg body weight/day by oral gavage between days 7 and 28 of gestation. The females were inseminated artificially with semen from eight proven males of the same strain, and ovulation was induced 1 hr later by an injection of 100 units of gonadotropin USP (Ayerst Laboratories, Inc., New York, NY). Semen from each male was used to inseminate an equal number of females in each group, and this procedure was performed on two consecutive days. The day of insemination with semen was designated day 0 of gestation. All the females were observed for Survival, clinical sign and body weight. Foetal body weight and Sexed were examined.

  One rabbits died each in 30 and 250 mg/kg bw/day including control. One rabbit aborted on day 28 of gestation at 250 mg/kg bw/day as compared to control. Pneumonia was observed in three rabbit which were died. Orange discoloration of the urine was observed in all the treated rabbits between days 7 and 28 of gestation as compared to control. No effect on body weight and body weight gain and No effect on Post-implantation loss/dam, Total implantations/dam and Corpora lutea/dam were observed in treated rabbits as compared to control. Similarly, there were no biologically meaningful or statistically significant differences in the number of litters, Foetal sex and gross pathological changes were observed in treated rabbits as compared to control. In addition, No effect on viability of foetus, foetal body weight and sex of foetus were observed as compared to control. At30 and 100 mg/kg be/day, malformations were observed in two foetuses from two litters. However, these values fell within the ranges of historical control data. There were no biologically meaningful or statistically significant differences in number of fetuses with malformations, number of foetuses or litters with developmental variations were observed in foetuses of any of the treated groups. Therefore, NOAEL was considered to be 250 mg/kg body weight /day for F0 and F1 generation when Dutch Belted female rabbits were treated with D&C YELLOW NO. 8 orally by gavage from day 6 to 27 of gestation.

  Thus, based on the above predictions and experimental study on Xanthylium, 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethyl-, molybdate tungstate phosphate (12224-98-5) and its structurally and functionally similar read across substance D&C YELLOW NO. 8 (518-47-8) in two different rodent species i.e rats and rabbits oral route, no adverse effects on reproductive and developmental parameter were observed. Thus, comparing this value with the criteria of CLP regulation Xanthylium, 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethyl-, molybdate tungstate phosphate (12224-98-5) cannot be classified as reproductive toxicant.

 

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

Thus, comparing this value with the criteria of CLP regulation Xanthylium, 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethyl-, molybdate tungstate phosphate (12224-98-5) cannot be classified as reproductive toxicant.